Project Summary Opioid use disorders (OUD) are a national public health emergency with more than 115 fatal overdoses occurring each day in the USA. Annually, the economic burden of OUD is over US$78 billion. Several medications are available for treating OUD, but their access is limited and efficacy is often sub-optimal. It is thus urgent to develop new and affordable strategies to treat OUD. Immunopharmacotherapy has emerged as a promising treatment approach against OUD. In contrast to traditional pharmacotherapies involving pharmacological agonists and antagonists of the opioid receptors, immunopharmacotherapy relies on drug specific antibodies to bind the circulating drug molecules to reduce their distribution to the brain, and thus reducing opioid-induced behaviors and toxicity. Vaccination is likely the safer and more cost-effective immunopharmacotherapeutic intervention, due to the ability of vaccines to trigger innate and adaptive immune responses in patients to offer long lasting protection against OUD. Due to their selectivity, vaccines are not expected to interfere with endogenous opioids nor with opioids used in pain management or treatment of OUD. Furthermore, it is possible to combine vaccines with current medications for more effective OUD treatment because of the different mechanism of action. Current anti-opioid vaccine candidates are primarily conjugate vaccines (opioid hapten-carrier protein conjugates) delivered in adjuvants for immune recognition. Although these conjugate vaccines have shown promising pre- clinical efficacy and selectivity against OUD, it is critical to test novel immunization platforms that may further improve vaccine efficacy against OUD. Hence, the goal of this project is to fabricate novel nanoparticle-based vaccines against OUD, which will likely lead to an effective immune response against the target opioid by offering these unique features: 1) efficient presentation of B cell and T cell epitopes, 2) improved uptake of vaccine particles by immune cells, and 3) incorporation of molecular adjuvants to promote a synergistic activation of adaptive immune pathways. The innovation of this project involves merging Dr. Zhang's uniquely structured lipid- polymer nanocarriers with Dr. Pravetoni's well-established opioid-based hapten series and pre-clinical platform to identify vaccine candidates. Development will be staggered across UG3/UH3 phases, and we expect to identify lead formulations of nanovaccines that offer protection against either oxycodone, fentanyl, or both at once. The broad impact of this project resides in the rational design of nanoparticle-based vaccines that are safe and effective against opioids. This novel nanoparticle-based immunization strategy can be applied to the development of next-generation vaccines against a range of OUD and other substance use disorders.